Carbamylbenzene stibonic acids



Patented June 3, 1952 CARBAMYLBENZENE STIBONIQ Norbert Steiger, Nutley, N. J., assigiior to Hoffmann-La Roche Inc., Roche Park, H a corporation of, New Jersey Nutley, N. J.,

No Drawing. Application J une 3, 1950, e 1 Serial No.'166,05'7

a 6 Claims. (Cl. 260447) This invention relates to para lower hydroxyalkylcarbamylbenzene stibonic acids and. meta and para lower hydroxyalkylaminoalkylcarbamylbenzen stibonic acids and the salts thereof, in which-the alkyl group in the hydroxyalkylcarbamyl radicals and the alkyl groups in the hydroxyalkylaminoalkylcarbamyl radical contain at leasttwo-carbon atoms. Illustrative of the lower hydroxyalkylcarbamyl and lower hydroxyalkylaminoalkylcarbamyl radicals are B-hydroxyethylcarbamyl, -'y-hydroxypropylcarbamyl, ,3- (p-hydroxy ethylamino)ethylcarbamyl, and the like. Some of the new acids combine with one molecule of water to form the corresponding monohydrates.

The new acids are water-insoluble but readily form solubl salts with bases in aqueous media. The resulting aqueous salt solutions are stable, and can be ampulled and heat sterilized for parenteral use. The new compounds are useful in the field of fungicides.

The new lower hydroxyalkylcarbamylbenzene stibonic acids and lower hydroxyalkylaminoalkylcarbamylbenzene stibonic acids can be prepared by diazotizing a para-amino-N- (lower hydroxyalkyDbenzamide or a metaor para-amino-N- (lower 'hydroxyalkylaminoalkyl)benzamide in which the alkyl groups contain at least two carbon atoms, and reacting the resulting diazonium compound with an antimonite, for example, sodium antimonite. The starting materials can be prepared by reacting a nitrobenzoyl chloride with a lower hydroxyalkylamine or a lower hydroxyalkylaminoalkylamine to form the corresponding nitro-N-(lower hydrox'yalkyl andlower hydroxyalkylaminoalkyl)-benzamides, and reducing the latter to form the corresponding amino-N-(lower hydroxyalkyl and lower hydroxyalkyl aminoalkyDbenzamides, as described in my application Ser. No. 143,150, filed February 8, 1950, now Patent No. 2,551,647, from which the following examples are taken.

7 EXAMPLE A benzamide ethylamino) ethanol and 60 grams of sodium carbonate there was added 186. gramsof p-nitrobenzoylchloride while stirring at 75-,9,0 C. The stirring was continued for 4 hours at"90 C. after which thereaction mixture was diluted with 1000 cc. of water... Upon standing for 16hours, crystals of p-nitro-N-[fi-(fi-hydroxyethylamino)- ethyl] -benzamide were formed. The crystals were filtered off and washed with three 100 cc. portions of ice water.

r 45 To 400 cc. of water, 125 grams of p-(fi-amino- 240 grams of iron filings, 700 cc. bf water and 10 cc. of acetic acid were refluxed ior'30 minutes and theprepared p-nitro-N- 3 (/3-hydroxyethyl' amino)ethy1]]oenz amide was added thereto at 90- -100 C; together with 150 cc..of waten jIh e mixture was refluxed for 4 hours and cc. ofJa 20% solution of sodium carbonate and 300 cc; of water added thereto at 90 C. 10 grams of afilter aid were added, the mixture was refluxed and then filtered at 95-100 C. The filter cake was washed with 500 cc. of boiling water, and the filtrate treated with 350 grams of sodium chloride and stirred I The p-amino-N-[fl-(B-hyd'roxyethylamino) ethyllbenzamide crystallized, M. P. 6 e

EXAMPLE B m-Amino N ss-hydromyethylammo) ethyl] benzamide H To 400 cc; of water, 125 grams of p-(fl-aminoethylamino). ethanol, and grams of sodium .carbonate there were added 186 grams of m-nitrobenzoylchloride with stirring-at -90? C. The stirring ,wasecontinued for 4rhours at Q-after which 1000 cc. of water were added to the reaction mixture. Upon standing for 16 hours, crystals of m-nitro-N-[ 8-(fi-hydroxyethy1amino) ethyllbenzamide were formed. They were filtered, and washed with three ccaportions of ice water; 230 grams of iron filings, 10 cc.'ofacetic acidand 500cc. of water were refluxed for 30 minutes and then. there was added thereto the above prepared m-nitro-N- [,6- (fi-hydroxyethylamino) ethyllbenzamide and cc. of water. The mixture was refluxed for 4 hours, and 55 cc. of 20% sodium carbonate and 300 cc. of wateradded thereto at 95-9'7 C. 10 grams of a filter aid were added, the mixture was refluxed, and then filtered at 95-100 C. The filter cake was washed with 500 cc. of boiling water and to the filtrate were added 350 grams of sodium chloride. The m-amino-Nr [,3- (fl-hydroxyethylamino) ethyl] benzamide was obtained as a viscousoil.

EXAMPLE 0 at-amino-N- ('3-hydroxypropyl) benzamide To 400 cc. of water, 67 grams of 3- amino-propanol and 70 grams of sodium carbonate there were added grams of p-nitrobenzoylchloride. The mixture was stirred for 2 hours at 90 C.,,thejn 400 cc. of a 30% solution of sodium chloride were added and the medium cooled to.15'C..-The mixture was then filtered to recover the ll-nitro- N (3 hydroxypropybbenzamide which 'had formed. The compound waswashedwithl three The following examples will illustrate the method of preparing the new :carbamylbenzene stibonio acid compounds.

EXAMPLE 1 7 19 grams of 4-amino-N-(2-hydroxyethyl) benzami'd'e were dissolved in dilute hydrochloric acid 'made up'of25 cc.-of concentrated (36%) "hydrofchlorica'cid and 125 cc. ozf water. The resulting solution waschilled to C.'and diazotized at 0 to '+5'C.-with asoluticn made upof '7 grams of "sodium nitrite and 35 cc. of Water. The clear-di- =azo solution was dropped into a slurry consisting of 24grams of antimony trioxide, 6000. of 40% 'sodiumhydroxide, '64 grams of glycerol, 150 cc. of -water and "1 'gramof 'copper powder, while agi- "tatedf'at -|-'l'5 to C. 'The reaction mixture was'thenstirredfor 4-hoursat room temperature 7 and neutralized with dilute hydrochloric acid made up "of 20 cc. (if-36% hydrochloric acid and 20 cc. of water. Carbon dioxide was then passed into the reaction mixtureuntil a pH of 7.5 was reached. Thereaction-mixture wasfiltered, the filtrate was acidified with hydrochloric'acidto congo, whereupon 4 0p hydroxyethylcarbamyl)- 'be'nzene-stibonic a'cid' precipitated. The precipitate wasp-filtered off-Fahd wasadded'to a mixture made-up of 250 "cc. of waterand 18 grams of oalmum carbonate powder. The resulting ;mixture "was =stirred for two hours and "then. filtered from *excess calcium carbonate. Thefiltrate was asolution 6f the calcium salt of 4- (fl-hydroxyethyl- 'cai'bamyll benzene'stibonic acid. The filtratezwas acidified with hydrochloricacid whereupon 4-(ohydroxyethylcarbamyll benzene stibonic acid "was cbtamed as a tan colored :p'owder iafterfiltrati'on and dr-ying in vacuo. The compound was combin'ed with o'nemolecule' of water. It :is readily soluble in dilute aqueous diethanolamine solu- 'tion. Thus, 3 grams of the stibonic acid were 'di'ssolved'lin cc. of a 5% :aqueous dieth'anola mine 'solution and 50cc. of water'at 50C. The resulting "solution was filtered and the filtrate diluted to I00 cc. This gave a 'stable 3% solution of 'the dietha'nolamine salt of 4- p-shydroxyethylcarbamyllbenzene"stibonic acid which could be "ampulled andheat sterilized.

EXAMPLE 2 78 grams of p-:amino-N-[B-(fl-hydroxyethylamino)ethyllbenzamideweredissolved in 105 cc. of concentrated (36%) hydrochloric acid and 600 cc. of water. The resulting solution was diazotizedwith a' solution of '30 grams of sodium nitrite in160 co. of'water at 0"to +5 C. The clear diazosolution was 'slowlyadded at +'15'to +23 C. withstirringtoa mixture or 70.jgrams of'antimony 't'rioxide; 1130 cc. of sodium'hydroxide "by volume), 130 gramsofglycerin'and300 cc.'of water. The reaction mixturewas stirred'rfor 5 hours at room temperature and carbon dioxide was introduced until the pH reached 7.5. The

reaction mixture was then filtered and the filtrate was acidified to congo with hydrochloric acid. The 4 [p (p-hydroxyethylamino) ethylcarbamyllbenzene stibonic acid was obtained as a white precipitate. v It was filtered, washed with water, and .driedlin vacuo at 0., yielding a light 'creamcol'ored powder. The compound obtained was combined with one molecule of water.

A stable 2% aqueous solution of the diethanol- :amine salt of :4-[49- (fl-hydroxyethylamino) ethylcarbamyllbenzene stibonic acid was prepared as follow-s:

v '-T2 'gramsof[theacid were added to cc. of waterandilOccxof'an'aqueous 10% diethanolamine solution. The :mixture was heated to -95".C.

untilssolution occurred. 2 cc. of 5% acetic acid were. added to neutralize the excess of diethanolamine. The resulting solution was filtered and the filtrate diluted to cc. It could be ampull'edand'heat sterilized.

EXAMPLE 23 grams of m-amino-N-[fi-(.c-hydroxyethylamino)-ethyl]benzamide weredissolved in cc. of waterand -35 cc. of 36% hydrochloric acid. The resulting solutionwas chilled 120.0 C. and diazotized-at 0C. with a-solution made up-of 8 grams ofsodium'nitrite and '60 cc. of water. The cleardiazosolution was-dropped intoa mixture made up of 16 grams of antimony'trioxidal gram of copper-powder, 50 ocuof 40% sodiumhydroxide,--3 2grams ofglycerol and'l50 cc. of .water'at +15 to- +25 :C. The reaction mixture was stirred .forabout5 hours at room temperature, then saturated-with carbon dioxide .untilithepH of the :reactionvmixtum was 7 .5. i I'he mixture was then .filteredand the filtrate acidified with hydrochloric acid to congo. The 3-[fl-(fi-hy droxyethylamino) ethylcarbamyl] benzene .stibonic-acid'wasobtained as-a white precipitate. It wasfiltered, washed with-cold water, and dried in vacuoat 40-50" C.

*One :gram of 3- B- 3-hydroxyethylamino) ethylcarbamyllbenzene stibonic acid, '5 cc. of..l0%

aqueous diethanolamine solution and 30 cc. of

water were heated to solution-at 80 C., and.2 cc. of- 5% 'acetic acid added thereto. The resulting solutionwasfiltered and the filtrate diluted 0050 cc. yielding a stable.2% :solution'of-the diethanolamine saltiof' 3 3- (flehydroxyethylamino) ethylcarbamyllbenzene. stibonic acid. .The solution could be-ampulled and heat sterilized.

EXAMPLE 4 "38 grams of 4-amino-N-(3 hydroxypropyl) beniamide'were dissolved in 800 cc. of waterand' 50 cc. of36'%'hydrochloric acid. The resulting solution was 'chilledto 5 C., and th'enidiazotized with a solution made up of 14 grams of sodium nitrite and 70 ccp'oi 'water'at 5' C. to +3 C. The clear 'diazo solution was .added slowly with agitation to a mixture made up of 35 grams of antimony trioxide, 65 grams of glycerol, '75 cc. of

' 40% sodium hydroxide and 150 cc. of Water-at The reaction mixture was stirred for! hours at room temperature and then saturated with car-- bon dioxide .until thempH was 55. The reaction mixture was then filtered and the filtrate acidified to 'congo with hydrochloric acid. .The 4-(3'-hy' 'droxypropylcarbamyl)benzene .stibonic .acid was obtained as a white precipitate. ..It was :filtered and dried in vacuo yielding a cream color powder. A 3% solution of diethanolamine salt of 4-(3hydroxypropylcarbamyl)benzene stibonic acid was prepared as follows:

3 grams of 4-(B-hydroxypropylcarbamyl)benzene stibonic acid, 7 cc. of 10% aqueous diethanolamine, and 60 cc. of water were heated to solution at 60 C. 2 cc. of 5% acetic acid were added and the solution filtered and diluted to 100 cc. The solution could be ampulled and heat sterilized.

Other bases, such as diethylamine, ammonium hydroxide, sodium carbonate, potassium carbonate, and the like, can be employed to produce aqueous solutions of the corresponding diethylamine, ammonium, sodium and potassium salts of the 4- (B-hydroxyethylcarbamyl) benzene stibonic acid, 4 [[3 (B-hydroxyethylamino)ethylcarbamyllbenzene stibonic acid, 3-[B-(fl-hydroxyethylamino) ethylcarbamyllbenzene stibonic acid, and 4-(3-hydroxypropylcarbamyl)benzene stibonic acid.

I claim: 7

1. A compound selected from the group consisting of para lower hydroxyalkylcarbamylbenzene stibonic acids and meta and para lower hydroxyalkylaminoalkylcarbamylbenzene stibonic acids in which the alkyl group contains at least two carbon atoms, the monhydrates thereof, and the salts thereof.

2. 4-(5 hydroxyethylcarbamyl)benzene stibonic acid monohydrate.

3. 4-[fi (p hydroxyethylamino)ethylcarbamyHbenzene stibonic acid.

4. 4-[p (p hydroxyethylamino)ethylcarbamyllbenzene stibonic acid monohydrate.

5. The diethanolamine salt of 4-(p-hydroxyethylcarbamybbenzene stibonic acid.

6. The diethanolamine salt of 4- [B- (fi-hydroxyethylamino) ethylcarbamyl] benzene stibonic acid.

NORBERT STEIGER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Schmidt Jan. 22, 1935 OTHER REFERENCES Number 1,988,632 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PARA LOWER HYDROXYALKYLCARBAMYLBENZENE STIBONIC ACIDS AND META AND PARA LOWER HYDROXYALKYLAMINOALKYLCARBAMYLBENZENE STIBONIC ACIDS IN WHICH THE ALKYL GROUP CONTAINS AT LEAST TWO CARBON ATOMS, THE MONHYDRATES THEREOF, AND THE SALTS THEREOF. 